2-oxadiazolechromone derivatives

Abstract

Novel compounds of the formula I in which R, X and n are as defined herein, are inhibitors of tyrosine kinase and can be employed for the treatment of tumours, for neuroprotection and for protection of the stress proteins of the skin.

1. A compound of formula I 
       
         
           
           
               
               
           
         
       
       in which
 R is A, 
 
       
         
           
           
               
               
           
         
         X is H, —OH, —OA, phenoxy, Ar, —O—CO-A, SO 3 H, SO 3 A, —OSO 3 H, —OSO 3 A, —OSO 2 A, SO 2 A, Hal, COOH, COOA, CONH 2 , NHSO 2 A, COA, CHO or SO 2 NH 2 , or 
         two radicals X together are methylenedioxy or ethylenedioxy, 
         R 1  is H, A, —OH, —OA or Hal, or two radicals R 1  together are methylenedioxy or ethylenedioxy, 
         Y is CH or N, 
         Ar is phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by A, 
         A is an unbranched or branched alkyl having 1-10 carbon atoms, in which 1-7 H atoms may be replaced by F, 
         Hal is F, Cl, Br or I, 
         n is 1, 2, 3 or 4, and 
         m is 1, 2, 3, 4 or 5, or 
         a salt or a solvate or a mixture of stereoisomers or isolated stereoisomer thereof. 
       
     
     
       2. A compound according to  claim 1 , in which
 X is H, —OH or —OA, or 
 two radicals X together are methylenedioxy or ethylenedioxy, or a salt or a solvate or a mixture of stereoisomers or isolated stereoisomer thereof. 
 
     
     
       3. A compound according to  claim 1 , in which
 R is A or 
 
       
         
           
           
               
               
           
         
          and 
         X is H, —OH or —OA, or 
         two radicals X together are methylenedioxy or ethylenedioxy, or a salt or a solvate or a mixture of stereoisomers or isolated stereoisomer thereof. 
       
     
     
       4. A compound according to  claim 1 , in which
 R is A, 
 
       
         
           
           
               
               
           
         
         X is H, —OH or —OA, 
         Y is N, 
         R 1  is A, 
         A is an unbranched or branched alkyl having 1-6 carbon atoms, 
         n is 1, 2, 3 or 4, and 
         m is 1, 2, 3 or 4, or 
         a salt or a solvate or a mixture of stereoisomers or isolated stereoisomer thereof. 
       
     
     
       5. A compound according to  claim 1 , in which
 R is 
 
       
         
           
           
               
               
           
         
         X is H, —OH or —OA, 
         R 1  is A, 
         A is an unbranched or branched alkyl having 1-6 carbon atoms, 
         n is 1, 2, 3 or 4, and 
         m is 1, 2, 3 or 4, or 
         a salt or a solvate or a mixture of stereoisomers or isolated stereoisomer thereof. 
       
     
     
       6. A compound according to  claim 1  selected from 6-hydroxy-2-[3-(4-tert-butylphenyl)-1,2,4-oxadiazol-5-yl]chromone, 7-hydroxy-2-[3-(4-tert-butylphenyl)-1,2,4-oxadiazol-5-yl]chromone, or 6-hydroxy-2-[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]chromone, a salt or a solvate or a mixture of stereoisomers or isolated stereoisomer thereof. 
     
     
       7. A pharmaceutical composition comprising a compound according to  claim 1  or a salt or a solvate or a mixture of stereoisomers or isolated stereoisomer thereof and one or more pharmaceutically acceptable excipients and/or adjuvants. 
     
     
       8. A food supplement comprising a compound of  claim 1 . 
     
     
       9. A cosmetic composition comprising a compound of  claim 1 . 
     
     
       10. A topically applicable cosmetic composition comprising a compound of  claim 1 . 
     
     
       11. A cosmetic composition according to  claim 9 , containing 0.000 1 to 50% by weight of a compound of  claim 1 . 
     
     
       12. A process for preparing a compound according to  claim 1  or a salt or a solvate or a mixture of stereoisomers or isolated stereoisomer thereof, comprising
 a) reacting a compound of formula II 
 
       
         
           
           
               
               
           
         
       
       in which
 X and n are as defined in  claim 1 , with a compound of formula III 
 
       
         
           
           
               
               
           
         
       
       in which
 A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, to give a compound of formula IV 
 
       
         
           
           
               
               
           
         
       
       in which
 X and n are as defined in  claim 1 , and A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, 
 b) then hydrolysing the compound of formula IV to a compound of formula V 
 
       
         
           
           
               
               
           
         
       
       in which
 X and n are as defined in  claim 1 , 
 c) then converting the compound of formula V to a compound of formula VI 
 
       
         
           
           
               
               
           
         
       
       in which
 X and n are as definedin  claim 1 , and then either reacting the compound of formula VI with a compound of formula VII 
 
       
         
           
           
               
               
           
         
       
       in which
 R is as defined in  claim 1 , to give a compound of formula I, or reacting the compound of formula V with a compound of formula VII 
 
       
         
           
           
               
               
           
         
       
       in which
 R is as defined in  claim 1 , in a two-step, one-pot reaction to give a compound of formula I, and/or 
 d) a compound of formula I is converted into a salt or into a solvate and/or a stereoisomer of a compound of formula I is isolated.